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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Investigations into the mechanisms of pyridine ring cleavage in vismodegib
S Cyrus Khojasteh1, Qin Yue, Shuguang Ma
1Department of Drug Metabolism and Pharmacokinetics (S.C.K., Q.Y., S.M., J.Z.C., T.M., R.T., J.L., C.E.C.A., H.W.), Department of Discovery Chemistry (G.C., J.L.), gRED Non Clinical Operations (K.M.), Small Molecule Pharmaceutical Sciences (W.J.), and Small Molecule Clinical Pharmacology (L.L.), Genentech Inc., South San Francisco, California.
Abstract:
Vismodegib (Erivedge, GDC-0449) is a first-in-class, orally administered small-molecule Hedgehog pathway inhibitor that is approved for the treatment of advanced basal cell carcinoma. Previously, we reported results from preclinical and clinical radiolabeled mass balance studies in which we determined that metabolism is the main route of vismodegib elimination. The metabolites of vismodegib are primarily the result of oxidation followed by glucuronidation. The focus of the current work is to probe the mechanisms of formation of three pyridine ring-cleaved metabolites of vismodegib, mainly M9, M13, and M18, using in vitro, ex vivo liver perfusion and in vivo rat studies. The use of stable-labeled ((13)C2,(15)N)vismodegib on the pyridine ring exhibited that the loss of carbon observed in both M9 and M13 was from the C-6 position of pyridine. Interestingly, the source of the nitrogen atom in the amide of M9 was from the pyridine. Evidence for the formation of aldehyde intermediates was observed using trapping agents as well as (18)O-water. Finally, we conclude that cytochrome P450 is involved in the formation of M9, M13, and M18 and that M3 (the major mono-oxidative metabolite) is not the precursor for the formation of these cleaved products; rather, M18 is the primary cleaved metabolite.
Insights
Vismodegib metabolism involves pyridine ring cleavage, forming metabolites M9, M13, and M18. Cytochrome P450 enzymes drive this process, with M18 identified as the primary cleaved product.
Area of Science:
- Pharmacology
- Drug Metabolism
- Biochemistry
Background:
- Vismodegib is an oral Hedgehog pathway inhibitor for advanced basal cell carcinoma.
- Metabolism is the primary route for vismodegib elimination.
- Previous studies identified oxidation and glucuronidation as key metabolic pathways.
Purpose of the Study:
- To elucidate the formation mechanisms of pyridine ring-cleaved vismodegib metabolites (M9, M13, M18).
- To investigate the specific roles of enzymes and intermediates in vismodegib metabolism.
Main Methods:
- In vitro, ex vivo liver perfusion, and in vivo rat studies were employed.
- Stable-labeled ((13)C2,(15)N)vismodegib was used to trace pyridine ring atoms.
- Trapping agents and (18)O-water were utilized to detect aldehyde intermediates.
Main Results:
- Carbon loss in M9 and M13 metabolites originated from the C-6 position of the vismodegib pyridine ring.
- The nitrogen atom in the M9 amide moiety was derived from the pyridine ring.
- Aldehyde intermediates were detected, and cytochrome P450 enzymes were implicated in the formation of M9, M13, and M18.
- M3, a major mono-oxidative metabolite, is not a precursor to these cleaved products; M18 is the primary cleaved metabolite.
Conclusions:
- Cytochrome P450 enzymes are crucial for the formation of pyridine ring-cleaved vismodegib metabolites M9, M13, and M18.
- M18 is identified as the principal metabolite resulting from pyridine ring cleavage.
- The findings provide detailed insights into the metabolic pathways of vismodegib.
